Heterogeneous addiction to TGFβ signalling in life threatening cSCC’s arising in RDEB patients


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Jasbani Dayal1,Andrew South2,Julio Salas-Alanis3,John McGrath4,Irene Leigh5,Karen Blyth6,Susan Mason6,Jemima Mellerio7,Christina Gruber8,Gareth Inman6
1Ninewells Hospital Medical School,2Thomas Jefferson University,3Universidad de Monterrey,4King's College London,5Queen Mary University of London,6The Beatson Institute for Cancer Research,7St John's Institute of Dermatology,8Paracelsus Medical University Salzburg

Abstract

Background

Recessive dystrophic epidermolysis bullosa (RDEB) is a hereditary skin fragility disorder characterised by sever blistering and chronic wounding. RDEB patients frequently develop invasive cutaneous squamous cell carcinomas (cSCC) that rapidly metastasise resulting in a high mortality rate of ~90% by the age of 55. Transforming Growth Factor β (TGFβ) signalling is elevated in RDEB cSCC but its role in RDEB tumourigenesis is still not understood. Here we test the response to inhibiting TGFβ signalling in RDEB cSCC and assess its use as a potential therapeutic strategy for these patients.

Method

Primary keratinocytes were isolated from RDEB cSCC patient material. The TGFβ type 1 receptor (TGFBR1) kinase inhibitor, SB-431542 , and TGFBR1 knockdown was used to test the effects of inhibiting endogenous TGFβ signalling on proliferation, clonogenicity, migration and invasion of RDEB cSCC keratinocytes (RDEB cSCCK) in vitro. Effects in-vivo were assayed in subcutaneous xenografts.

Results

Proliferation, clonogenic potential, migration and invasion of 50% of RDEB cSCCK’s (n=3/6) was inhibited upon inhibition of endogenous TGFβ signalling. However, inhibition of TGFBR1 activity could also promote proliferation and clonogenicity of RDEB cSCCK’s (n=1/6) whilst having no effect on others (n=2/6). In-vivo experiments confirmed our in-vitro findings where overall survival of SCID mice subcutaneously injected with TGFBR1 addicted cells that were inhibited in in-vitro assays was significantly enhanced following pre-treatment with SB-431542 compared to vehicle control. Similarly, SCID mice injected with cells promoted by SB-431542 in in-vitro assays tended to reach clinical endpoint earlier when pre-treated with SB-431542 compared to vehicle control.

Conclusion

Inhibiting TGFBR1 signalling has potential therapeutic benefits for only a subset of RDEB cSCC patients and any clinical use of TGFBR1 inhibitors should proceed with caution due to possible tumour promoting effects of TGFβ in a subset of these patients.